Cell cycle-dependent mRNA localization in P-bodies
Posted on: 11 July 2024 , updated on: 12 July 2024
Preprint posted on 16 April 2024
Article now published in Molecular Cell at http://dx.doi.org/10.1016/j.molcel.2024.09.011
P-bodies are more than just storage sites for translationally repressed mRNAs and RNPs
Selected by Mohammed JALLOH
Categories: cell biology, molecular biology
Why I picked this preprint
I chose to highlight this preprint because it provides a comprehensive analysis of the dynamic behavior of P-bodies and their role in mRNA regulation throughout the cell cycle. The authors use advanced techniques like Fluorescence Activated Particle Sorting (FRAPS), RNA sequencing, and single-molecule fluorescence in situ hybridization (smFISH) to offer new insights into the interplay between P-bodies, mRNAs, and the cell cycle. Understanding these interactions is crucial for understanding the mechanisms of post-transcriptional gene regulation.
Background
Processing bodies (P-bodies) are cytoplasmic, non-membrane-bound ribonucleoprotein (RNP) granules primarily composed of translationally repressed mRNAs and RNA-binding proteins (RBPs) involved in RNA metabolism and decay (Brothers et al., 2022; Luo et al., 2018). They are constitutively present in mammalian cells and play crucial roles in post-transcrptional regulations (Luo et al., 2018). P-bodies (PBs) contain enzymes and proteins associated with mRNA turnover, including those involved in mRNA decay, nonsense-mediated decay, AU-rich element-mediated decay, and microRNA (miRNA)-induced silencing (Brothers et al., 2022; Peng et al., 2021; B. Wang et al., 2021). Initially thought to be storage sites for translationally repressed mRNAs, recent studies suggest that PBs may also function as sites for mRNA decay (Blake et al., 2024; C. Wang et al., 2018). The formation, function, and clearance of these granules in various biological contexts remain an active area of research.
Study overview
In this preprint, Safieddine and colleagues investigated the evolution of P-bodies during different phases of the cell cycle by examining how specific mRNAs are recruited to PBs at differrent cell cycle stages.
P-Bodies morphology and cell cycle progression
To investigate the interplay between PBs, mRNA, and the cell cycle, the researchers examined PBs (morphology) during different cell cycle phases. Immunofluorescence staining against the classic PB marker DDX6 showed that PB size and DDX6 intensity increased from G1 – G2 (Fig1A-B). Despite this enlargement, the number of PBs per cell increased modestly, and protein composition remain relatively unchanged. Proteomic analysis showed consistent levels of major PB proteins, with miRNA pathway proteins enriched and mitochondria proteins and translation initiation factors depleted across the cell cycle.
RNA Length and PB Localization
To investigate factors responsible for RNA localization to PBs, the researchers used mRNAs of varying lenghts and found that mRNA localization to PBs varies independently of cytoplasmic abundance, indicating a regulatory role for PBs in gene expression throughout the cell cycle. They discovered that mRNA length, including coding sequences (CDS) and untranslated regions (UTRs), influences mRNA localizations to PBs during the G1 phase. This suggests certain RBPs may preferentially bind longer mRNAs in a cell-cycle dependent manner, affecting their PB localization.
Translation Inhibition Effects and Dynamic mRNA Localization Patterns
Next, the researchers investigated the localization mechanism of specific mRNAs (BUB1B, TOP2A, CENPF) in PBs during different cell cycle phases, particularly in response to translation inhibition by puromycin. Indeed, puromycin treatment significantly increased the fraction of these mRNAs in PBs during early G1 and S/G2 phases (Fig4E), but this did not fully explain the cyclic patterns observed throughout the cell cycle. Disrupting polysomes did not prematurely drive these mRNAs into PBs in G2, suggesting other factors beyond translation status influence mRNA localization to PBs.
Additionally, they characterized the dynamic localization patterns of various cell cycle regulator proteins mRNAs (FBXO5, CLK1, and CCNE2) in PBs throughout the cell cycle. FBXO5 mRNA peaked in PBs during G1/S and mid S phases, indicating a role in cell cycle transitions and genome intergrity. CLK1 mRNA levels gradually incrased in PBs and the cytoplasm, peaking at G2/M, suggesting involvement in alternative splicing and cell cycle regulation. CCNE2 showed maximal levels in PBs and the cytoplasm during G1/S, relfecting its critical function in G1/S transitions and DNA replication initiation. Taken together, this indicate PBs are crucial cell cycle and gene expression regulators.
Conclusion
These varied localization patterns highlight the complex, gene-specific regulation of mRNA localization in PBs across different cell cycle phases, contributing to the precise control of cellular processes. This study underscores the importance of understanding the dynamic interactions between PBs, mRNAs, and the cell cycle to unravel the regulatory mechanisms governing post-transcriptional gene expression.
Key Contributions
- The findings in this preprint highlight the additional functions of PBs in the cell and that these organelles are not just storage sites for excess untranslated mRNAs suggesting a role in post-mitotic PB reassembly.
- The findings also emphasize that mRNA accumulation in PBs can be influenced by intrinsic factors—like GC content and mRNA length—as well as extrinsic factors, like RBPs.
- The study also reveals that mRNAs in PBs tend to be longer than average, with higher correlation in the G1 phase of the cell cycle.
Questions/Future Directions
- What other factors, besides translation inhibition, influence the cyclic localization patterns of specic mRNAs in P-bodies?
- Do the authtors intend to investigate how the localization of specific mRNAs to P-bodies impacts their functional roles in the cell cycle?
- What specific RBPs prefentially bind to longer mRNAs in a cell cycle-dependent manner, and how do they influence localization to P-bodies?
Bibliography
- Blake, L. A., Watkins, L., Liu, Y., Inoue, T., & Wu, B. (2024). A rapid inducible RNA decay system reveals fast mRNA decay in P-bodies. Nature Communications, 15(1), 2720. https://doi.org/10.1038/s41467-024-46943-z
- Brothers, W. R., Fakim, H., Kajjo, S., & Fabian, M. R. (2022). P-bodies directly regulate MARF1-mediated mRNA decay in human cells. Nucleic Acids Research, 50(13), 7623–7636. https://doi.org/10.1093/nar/gkac557
- Loll-Krippleber, R., & Brown, G. W. (2017). P-body proteins regulate transcriptional rewiring to promote DNA replication stress resistance. Nature Communications, 8(1), 558. https://doi.org/10.1038/s41467-017-00632-2
- Luo, Y., Na, Z., & Slavoff, S. A. (2018). P-Bodies: Composition, Properties, and Functions. Biochemistry, 57(17), 2424–2431. https://doi.org/10.1021/acs.biochem.7b01162
- Peng, P.-H., Hsu, K.-W., & Wu, K.-J. (2021). Liquid-liquid phase separation (LLPS) in cellular physiology and tumor biology. American Journal of Cancer Research, 11(8), 3766–3776.
- Wang, B., Zhang, L., Dai, T., Qin, Z., Lu, H., Zhang, L., & Zhou, F. (2021). Liquid–liquid phase separation in human health and diseases. Signal Transduction and Targeted Therapy, 6(1), 1–16. https://doi.org/10.1038/s41392-021-00678-1
- N., & Spang, A. (2018). Context-dependent deposition and regulation of mRNAs in P-bodies. eLife, 7, e29815. https://doi.org/10.7554/eLife.29815
doi: https://doi.org/10.1242/prelights.37876
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